Investigating the Role of Noncanonical Tricarboxylic Acid Metabolism in Kidney Cancer
Abstract
Background: Despite recent advances in kidney cancer treatment, kidney cancer remains the 8th most common cancer with approximately 63,000 new cases and approximately 14,000 fatalities each year in the United States alone, devastating patients, their families and friends, and communities, among whom many are current or former military personnel. Renal cell carcinoma (RCC) accounts for greater than 90% of cancers detected in the kidney. This encompasses a large heterogeneous group of cancers all derived from renal tubular epithelial cells, but of these, clear cell renal cell carcinoma (ccRCC) is the most common (70%-75% of kidney cancer) and aggressive subtype of kidney cancer. In patients impacted by ccRCC, metastasis, the process by which cancer cells spread from the primary tumor to distant locations in the body, is responsible for most deaths. Despite this long-standing observation, the mechanisms that cause kidney cancer to spread to distant locations in the body remains largely unknown. In this grant application, we focus on SETD2, a gene that is commonly mutated in ccRCC and associated with kidney cancer metastasizing to distant organs. Our goal is to investigate the mechanisms by which SETD2 mutations promote kidney cancer metastasis and specifically, we will investigate whether SETD2 mutations alter cell metabolism in ways that make it easier for kidney cancer cells to spread and colonize these metastatic sites. Areas of Emphasis: Cancer metabolism; cancer genetics. Impact and applications: Metabolism is fundamental to tumor cell growth. To meet the biosynthetic challenges of continued cell proliferation, cancer cells must accumulate biomass either through biosynthetic reactions or by scavenging nutrients from the environment. When cells that leave the primary tumor site and disseminate for tumor metastases in other parts of the body cells it marks a critical transition into more aggressive disease. Recently, understanding the nutrient acquisition and metabolism of cancer cells in these settings has become an area of intense focus as this represents one of the major challenges these cells overcome. In ccRCC, SETD2 mutations are associated with more aggressive and metastatic cancers our preliminary data indicates that loss of SETD2 also results in dramatic alterations in cellular metabolism. We believe these metabolic changes may be required to support the metastatic dissemination of cells from the primary to distant sites. Our interest in studying this metabolic transition is therefore to identify pathways that tumor cells are particularly reliant upon, more so than other non-tumor cells in the body. Such pathways then become targets which could be inhibited therapeutically. Our research will pave the way for the application of new therapeutic strategies aimed at targeting nutrient utilization and metabolic enzymes in cancer. To generate these insights, we will leverage several complementary approaches to assess kidney cancer metabolism in cells with and without mutant SETD2 protein. Our study is designed to provide mechanistic insights which will have broad impact on cancer biology beyond kidney cancer. In the long term, we expect our elucidation of SETD2-driven metabolic changes will pave the way for the future discovery of therapeutic strategies for SETD2-mutated cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310986
Entities
People
- Justin Cross
Organizations
- Sloan-Kettering Institute
- United States Army